Management of BK Polyomavirus in a Kidney Transplant Recipient With Primary Myelofibrosis on JAK-2 Inhibition – A Case Report and Literature Review

Abstract

The use of Janus Kinase (JAK) inhibitors with concomitant maintenance immunosuppressive therapy (IST) for the solid organ transplant (SOT) population presents significant challenges due to intensified immunosuppression resulting in an increased risk of opportunistic infections and malignancies coupled with limited clinical experience among transplant providers. A 48-year-old man presented with end-stage kidney disease secondary to IgA nephropathy requiring commencement of haemodialysis. He had a concurrent diagnosis of primary myelofibrosis (PMF), which did not require treatment at presentation. A year later, he underwent a living-donor kidney transplant from an HLA-identical sibling. The patient received induction IST with basiliximab and methylprednisolone, followed by standard maintenance therapy with tacrolimus and mycophenolate mofetil. The latter was reduced in dose due to underlying PMF. In the months following transplantation, he experienced worsening PMF parameters and was commenced on the JAK2 inhibitor, ruxolitinib. This was complicated by development of detectable BK Polyomavirus DNA (BKPyV-DNAemia), prompting adjustment of his immunosuppression regimen and dose reduction of ruloxlitinib. His course was further complicated by renal allograft rejection. Ruxolitinib was subsequently discontinued, and he transitioned to the second-generation JAK inhibitor fedratinib, which led to improvement in PMF parameters and stabilization of both graft function and BKPyV-DNAemia. This case highlights the therapeutic challenges inherent in integrating JAK inhibitors into established immunosuppression regimens in solid organ transplantation. It underscores the difficult balance between preserving graft tolerance and mitigating the risk of opportunistic infections such as BKPyV-DNAemia, while emphasising the need for close monitoring of net immunosuppression in this setting.

Introduction

The use of Janus Kinase (JAK) inhibitors for autoimmune and hematologic disorders has grown over the last decade with expanding applications. ¹ As a result, JAK inhibitors are more likely to be encountered among solid organ transplant (SOT) recipients, though there is limited data on use in this population. JAKs are crucial intracellular components of cytokine receptors. Inhibition results in down-stream alterations to cellular activity and blocking this pathway offers therapeutic advantages in immune disorders. However, safety concerns with accentuated immunosuppression exists for patients on concurrent immunosuppressive therapy (IST), such as SOT recipients, due to increased risk of opportunistic infections and malignancy.^2-4 Here, we describe a kidney transplant recipient treated with a JAK2 inhibitor for primary myelofibrosis (PMF) while on standard post-transplant IST who developed BKPyV-DNAemia.

Presenting Concerns

A 48-year-old male presented to the Emergency Department with loss of appetite and fatigue. He was found to have kidney failure (creatinine 857 μmol/L, eGFR of 6 mL/min) with leucocytosis (white blood cells 20 x 10^9/L), thrombocytosis (platelets 917 x10^9/L), and splenomegaly. He required initiation of haemodialysis shortly after presentation. A kidney biopsy was performed which demonstrated IgA nephropathy (Oxford Classification: M0 E0 S1 T2 – C0) with severe chronic changes. A bone marrow biopsy revealed low-risk JAK 2-positive PMF at an overt fibrosis stage. ⁵

The patient was referred for kidney transplant assessment, with a potential living donor identified in his HLA-identical sibling. He was also reviewed by the Bone Marrow Transplant team, who deemed a bone marrow transplant unnecessary given the favourable prognosis of his PMF. He was subsequently approved for kidney transplantation. Other comorbidities included hypertension, alpha-thalassemia minor, splenomegaly secondary to myelofibrosis, and a right internal jugular thrombus related to dialysis access for which he remained anticoagulated until transplantation. In December 2021, one year after initial presentation, the patient underwent an HLA-identical (18/18 match) living-donor kidney transplant from his sibling. Pre-transplant evaluation showed a panel reactive antibody of 0%, Cytomegalovirus (CMV) seronegativity in both donor and recipient, and an Epstein-Barr virus (EBV) mismatch (donor positive, recipient negative). Induction immunosuppression comprised basiliximab with rapid steroid withdrawal, followed by maintenance therapy with tacrolimus (trough target 6-8 ng/mL) and mycophenolate mofetil (MMF) 750mg twice daily. This regimen was chosen given the patient’s low immunologic risk and underlying primary myelofibrosis (PMF). Post-transplant, graft function was excellent (creatinine 125 μmol/L). At three months, the MMF dose was reduced to 500mg twice daily in view of his PMF, and he remained clinically stable on this adjusted regimen alongside trimethoprim-sulfamethoxazole prophylaxis.

Clinical Findings

In the first few months post-transplant, the patient demonstrated progressive deterioration in PMF parameters, with haemoglobin levels of 150 – 160g/L, a white blood cell count of 19 x 10^9/L, and platelets rising to 900 x 10^9/L by four months post-transplant (Figure 1). Shortly thereafter, the patient presented to the emergency department with abdominal pain and was found to have worsening splenomegaly. On Haematology review, low-dose aspirin was initiated, and ruxolitinib was commenced five months post-transplant at 5mg twice daily. The dose was gradually titrated to 15mg twice daily by seven months post-transplant, allowing discontinuation of intermittent phlebotomy and normalization of complete blood count parameters by 8 months post-transplant (see Table 1 for detailed timeline).

Figure 1.

Longitudinal course of graft function, immunosuppressive therapy, BKPyV viral load, and hematologic parameters post kidney transplant

BKPyV viral load (BK polyomavirus viral load) is expressed as log₁₀ copies/mL. Immunosuppressive therapy includes tacrolimus, mycophenolate mofetil (MMF), prednisolone, and Janus Kinase inhibitors (ruxolitinib and fedratinib). Doses are presented in milligrams (mg). Key treatment modifications are shown

Table 1.

Timeline of Immunosuppression and BKPyV-DNAemia Post-kidney Transplantation

Date	Event
Month 16 pre-transplant	• Initial presentation with kidney failure (eGFR 6 mL/min), leucocytosis, thrombocytosis, splenomegaly; • Started hemodialysis.
Month 15 pre-transplant	• Kidney biopsy confirmed IgA nephropathy with severe chronic changes.
Month 14 pre-transplant	• Bone marrow biopsy diagnosed low-risk JAK2-positive PMF.
Month 11 pre-transplant	• Assessment by BMT team - PMF felt to have good >10 yr prognosis and not advanced enough to require treatment.
Month 8 pre-transplant	• Assessed by Primary Transplant Centre. • Approved to proceed with living donor transplantation.
Month = 0 (transplant)	• HLA-identical kidney transplant from sibling with immediate graft function. • Basiliximab induction, tacrolimus target 6-8 ng/mL, MMF 750 mg BID.
Month 3 post-transplant	• Transferred to Regional Transplant Program • MMF reduced to 500 mg PO BID at time of transfer. • Tacrolimus target 5-7 ng/mL
Month 1 - 3 post-transplant	• Deterioration of PMF parameters (Hb 118 g/L – 139 g/L, Hct 0.35 – 0.50 L/L); increased WBC (15 - 17 x 10^9/L) and platelets (520 - 1031 x 10^9/L).
Month 4 post-transplant	• ER presentation with abdominal pain and found to have worsening splenomegaly; • Started aspirin. • Intermittent phlebotomies.
Month 5 post-transplant	• Started Ruxolitinib at 5 mg BID
Month 7 post-transplant	• Ruxolitinib increased to 15 mg PO BID
Month 8 post-transplant	• CBC parameters normalized
Month 11 post-transplant	• BKPyV-DNAemia detected at 1080 copies/mL
Month 12 post-transplant	• MMF reduced to 500 and 250 mg PO BID for rising BK viral load • MMF further reduced to 250 mg PO BID • MMF held due to rising BK viral load (19,100 copies/mL). • Tacrolimus target reduced ∼5 ng/mL.
Month 13 post-transplant	• BKPyV viral load 30,000 copies/mL; low-grade EBV viremia detected. • Renal Allograft Biopsy performed for increasing creatinine and BKPyV-DNAemia. • Reviewed by Primary Transplant Centre and Hematology. • Ruxolitinib reduced to 10 mg BID.
Month 15 post-transplant	• BKPyV viral load peak 130,000 copies/mL. • Ruxolitinib reduced to 5 mg BID. • Ruxolitinib stopped.
Month 16 post-transplant	• BKPyV viral load improves off MMF and JAK2 inhibitor (tacrolimus monotherapy). BKPyV viral load stable (∼40,000 copies/mL). • Worsening CBC parameters. • Case reviewed by Myeloid Specialist and special access for fedratinib applied for. • Creatinine worsening (138 – 166 µmol/L)
Month 17 post-transplant	• Renal Allograft Biopsy #2. • 1B Acute cell-mediated rejection. • Treated with pulse steroids (methylprednisolone 500 mg IV daily x 3 days, then rapid taper to prednisone 20 mg daily to complete 1 month, followed by slower taper 5 mg weekly until 5 mg daily). • Prednisone 5 mg daily indefinitely. • Creatinine improved to 131 µmol/L. • BKPyV viral load decreased to low level (3630 copies/mL).
Month 19 post-transplant	• Fedratinib started at 200 mg daily. • Fedratinib increased to 300 mg daily.
Month 22 post-transplant	• Fedratinib briefly increased to 400 mg daily.
Month 23 post-transplant	• Fedratinib reduced to 300 mg daily
Month 26 post-transplant	• Fedratinib reduced to 200 mg due to improved erythrocytosis and maintained improvement in splenomegaly.
Month ∼36 post-transplant - present	• Stable graft function (creatinine 115 -135 µmol/L); low-grade BKPyV-DNAemia (<1000-2000 copies/mL); stable PMF parameters (Hb ∼130 g/L, Hct 0.42 L/L Platelets ∼400-500 x 10^9/L). • Immunosuppression: Tacrolimus target 5-7 ng/mL, Prednisone 5 mg daily, Fedratinib 200 mg daily

JAK: Janus Kinase, PMF: Primary Myelofibrosis, BMT: Bone Marrow Transplant, MMF: Mycophenolate mofetil, Hb: Hemoglobin, Hct: Hematocrit, WBC: White Blood Cell, ER: Emergency Room, CBC: Complete Blood Count, BKPyV-DNAemia: BK Polyomavirus DNA detectable in blood, EBV: Epstein Barr Virus.

Diagnostic FOCUS and Assessment

By eleven months post-transplant, as part of routine screening, BK polyomavirus was detected in the patient’s serum (1080 copies/mL). Graft function at this time was stable. Despite progressive adjustment of immunosuppression, including sequential reduction and eventual cessation of MMF and lowering of the tacrolimus trough target (4 – 6 μg/L), BKPyV viral load continued to rise. By thirteen months post-transplant, the viral load had increased to approximately 30,000 copies/mL, accompanied by low-grade EBV viremia. In consultation with the Haematology team, the ruxolitinib dose was reduced to 10mg twice daily. There was a subsequent rise in serum creatinine from 125 to 162μmol/L. Donor-specific antibodies were absent. Renal biopsy revealed no evidence of rejection or BKPyV-nephropathy, although due to the patchy nature of this disease - BKPyV-nephropathy could not be entirely excluded. The biopsy also demonstrated mild mesangial immune complex deposition below the diagnostic threshold for recurrent IgA nephropathy.

Therapeutic FOCUS and Assessment

With escalation in BKPyV viral load to 130,000 copies/mL despite IST adjustments, ruxolitinib was reduced further to 5mg twice daily at sixteen months post-transplant. BKPyV viral load declined but remained elevated (80,000 copies/mL) and so ruxolitinib was ceased (Figure 1). Intravenous immunoglobulin was considered per the local treatment protocol, though fortunately the BKPyV-DNAemia began to improve shortly after ruxolitinib discontinuation, and IVIG was ultimately not required. At 17 months post-transplant while on tacrolimus monotherapy, the patient developed an acute rise in serum creatinine to 166μmol/L. Repeat renal biopsy demonstrated acute cell mediated rejection (Banff 2024 IB –i2, t2, v0, g0, ptc1, C4d0) with negative SV40 staining and polyomavirus score of zero. Inflammatory changes were felt less likely to reflect acute interstitial nephritis in the absence of systemic symptoms (peripheral eosinophilia, rash or leukocyturia) and the lack of potential offending medication. He was treated with intravenous methylprednisolone 500 mg daily for three days, followed by a rapid taper to 20 mg daily for one month, and then a gradual weekly taper to 5 mg daily. BKPyV-DNAemia remained stable at approximately 40,000 copies/mL during steroid therapy and subsequently declined to low level detection (1620 copies/mL) by nineteen months post-transplant. With stabilized graft function, low-grade BKPyV-DNAemia, and improvement in hematologic parameters, JAK2 inhibition was reintroduced. Through special access, fedratinib was commenced at a dose of 200 mg daily. This second-generation JAK inhibitor displays greater JAK2-selectivity and is associated with a lower risk of opportunistic viral infections.^4,6 The dose was titrated according to hematologic response while closely monitoring serum BKPyV-DNA levels. It was increased to 300 mg daily at twenty months post-transplant, briefly escalated to 400 mg daily at twenty-three months post-transplant, then reduced to 300 mg a month later, and subsequently to 200 mg daily just over two years post-transplant following an improved erythrocytosis response.

FOLLOW-UP and Outcomes

As of three years post-transplant, the patient continues to have low-grade BKPyV-DNAemia (1000-2000 copies/mL; 1300 copies/mL most recently) with stable PMF parameters, EBV and JC virus remain undetectable. He is maintained on fedratinib 200 mg daily, tacrolimus (Advagraf) 2 mg daily, and prednisolone 5 mg daily, with stable graft function (creatinine 121 μmol/L, eGFR 59 mL/min). The ongoing management focus is to sustain hematologic stability while minimizing over-suppression of immune function to prevent recurrence of high-level BKPyV-DNAemia and other opportunistic infections.

Discussion

In recent years, the therapeutic landscape for immune-mediated and inflammatory diseases has expanded significantly with a growing focus on agents that precisely target inflammatory pathways. This has seen JAK inhibitors become more prevalent in use. JAK inhibitors are transmembrane receptors that respond to specific cytokines. On activation, down-stream signalling is via signal transducers and activators of transcription (STAT) proteins. The JAK-STAT pathway is central in driving proinflammatory responses, including proliferation, differentiation, and apoptosis. Located primarily on immune cells and hematopoietic cells, different JAK isoforms (JAK 1, 2, 3, TYK2) can be inhibited to selectively modulate the immune response. ⁴ There are several known challenges associated with JAK inhibitors that are important for informed use. A large post-marketing surveillance trial of JAK inhibitor use in rheumatoid arthritis identified a higher risk of major adverse cardiac events, malignancy, and viral infections (particularly of the Herpesviridae family). ⁷ Compared to other biologic Disease-Modifying Antirheumatic Drugs (bDMARDs), there was a similar increased risk of respiratory and urinary tract infections, along with an observed increased risk of reactivation of latent infections including hepatitis B virus (HBV) and Mycobacterial tuberculosis. ⁷ There are limited small trials and case reports on how these risks may be amplified in the setting of concurrent IST beyond the use of concurrent conventional synthetic DMARDS (such as methotrexate) utilised in rheumatologic conditions.^8-10

The most informed use of JAK inhibitor with standard post-transplant IST can be taken from early trials assessing tofacitinib as an alternative to calcineurin inhibitor (CNI) therapy along with mycophenolate and prednisolone in renal transplant recipients.^2,3,10 In the pilot trial, whilst there were non-inferior outcomes in graft function at six months, there were notable safety concerns with higher rates of viral infections (BKPyV nephropathy and cytomegalovirus disease) compared with CNI use, particularly with higher doses of tofacitinib (30 mg vs. 15 mg). ² Cytopenia was also more frequently seen in the tofacitinib group. Furthermore, a Phase IIb trial demonstrated that tofacitinib use resulted in higher rates of serious infection, and post-transplant lymphoproliferative disorder (PTLD). ¹⁰ An extension of this trial identified that this risk was greatest with higher doses. ³ Mechanistically, combining a JAK inhibitor with other immunosuppressive agents likely amplifies oncogenic and infectious risk by attenuating T-cell responses, reducing NK-cell surveillance, and blunting type I/II interferon signally which are all key to anti-tumour and anti-viral activity. ¹¹

Observed use of JAK inhibitors in other disorders have demonstrated that these medications demonstrate dose-dependent selectivity. At lower doses, agents like baricitinib primarily target JAK1 and JAK2. However, higher doses result in broader activity, inhibiting additional JAK isoforms. ¹² While this can enhance therapeutic effects, adverse or off-target effects can similarly be increased. There is scarce information in the literature to inform dosing in the SOT population, including whether to maintain or reduce the dose, and the safety of long-term treatment is unclear.^7,13

Case reports of JAK inhibitor use in other SOT recipients highlight the need for dose adjustment when combined with usual post-transplant maintenance IST. For example, a recent case report of a 44-year-old liver transplant recipient developed JAK2 V617F positive PMF and was initially started on ruxolitinib (15 mg twice daily), along with tacrolimus and mycophenolate. The patient developed pancytopenia, prompting a dose reduction to 5 mg twice daily. Following the adjustment, no infectious complications occurred, and the myelofibrosis remained controlled. ⁹

In our case, high dose ruxolitinib enhanced total net IST with the opportunistic development of BKPyV-DNAemia eleven months into treatment. Current international consensus guidelines recommend monthly BKPyV-DNAemia screening until 9 months post-transplant, followed by 3-monthly monitoring until 2 years, after which surveillance is generally not recommended in stable recipients, with the caveat that monthly screening should be resumed for 3 months after intensification of immunosuppression. ¹⁴ In our case, a JAK inhibitor was introduced at 5 months post-transplant, aligning with a period of intensified surveillance; however, BKPyV-DNAemia developed at 11 months, beyond the recommended period of extended monthly surveillance. This highlights a potential limitation of current recommendations, suggesting that delayed reactivation may occur with novel immunosuppressive therapies. Consideration should be given to more frequent BKPyV-surveillance in the setting of JAK inhibition.

Additionally, the BKPyV-DNAemia occurred despite proactive reduction in his standard maintenance post-transplant IST. This unintended side effect was managed with dose adjustment, although with severe infections, JAK inhibitors are typically discontinued. It should be noted that abrupt cessation of ruxolitinib and perhaps other JAK inhibitors can result in “ruxolitinib discontinuation syndrome,” characterized by rapid relapse of disease symptoms and, in severe cases, a cytokine storm.^6,15 In our case, the dose was gradually tapered avoiding any withdrawal symptoms. This slow taper may partially explain the slow resolution of the observed BKPyV-DNAemia.

Beyond infectious issues, this case was further complicated by the occurrence of biopsy-proven T cell-mediated rejection. This was noteworthy given the HLA-matched (18/18) donor-recipient pairing in which the risk of rejection even with reduced CNI exposure would have been low. This unexpected outcome highlights the complexity of immune regulation under combined immunosuppressive therapies. While JAK inhibition is known to increase susceptibility to opportunistic infections and viral reactivation ⁷ the effects on alloimmune responses are less well characterized. Data from oncological studies indicate that JAK/STAT signalling can have context-dependent roles in both tumour progression and anti-tumour immunity, likely driven in part by crosstalk with other immune pathways. ⁴ This pleotropic activity raises the possibility of off-target effects on immune regulation, including alloreactivity. In this case, concurrent BKPyV-DNAemia and ongoing adjustments to immunosuppression may have contributed to immune dysregulation, thereby lowering the threshold for rejection despite favourable immunological matching.

Newer second-generation JAK inhibitors provide more selectivity. The activity of ruxolitinib is non-specific to the observed JAK 2V617F mutation associated with PMF. It’s efficacy in this setting likely stems from suppression of the constitutively active JAK/STAT pathway, leading to myelosuppression. ⁴ Fedratinib, a newer JAK inhibitor and second line agent for PMF, specifically targets JAK2 associated with hematopoietic cells, comparatively reducing the broader immunosuppressive effects observed with ruxolitinib which targets both JAK 1 and 2.^4,6

When JAK inhibitors are utilised in the transplant setting, drug-drug interactions must also be considered. Small studies have suggested no interaction with MMF. ¹⁶ However, most JAK inhibitors use the metabolic pathway involving the cytochrome P450 system and have the potential for competitive inhibition of enterohepatic recirculation. ¹⁷ Therapeutic drug monitoring with post-dose serum levels in patients on other IST agents to prevent overexposure has been considered. ¹⁷ However, the brief half-life of these agents may still render such measurements imprecise.^17,18 Additionally, JAK inhibitors exhibit a narrow therapeutic index and significant inter-individual variability to drug exposure. Other monitoring strategies described in randomized control studies are diverse and specifically aligned with their unique study goals. Biomarker monitoring, such as STAT levels, has been proposed to indirectly signal the drug’s presence, though this method lacks sufficient validation or reliable implementation. ¹⁹ Currently, pharmacodynamic correlations with indicators like immune cell counts and viral load assessments serve as the principal means to gauge the extent of immunosuppression.^18,19 However, the development of specific assays for rapid therapeutic drug monitoring may be promising. ²⁰

In summary, our case contributes to the growing body of literature surrounding JAK inhibitor use in the SOT population, highlighting the additional immunosuppressive effects of JAK inhibitors and the increased risk of opportunistic infections with these agents. This case demonstrates the importance of considering the impact of JAK inhibitor use on net IST in the management of BKPyV-DNAemia and of possible off-target effects. The long-term implications of JAK inhibitor use in kidney transplantation are unclear. This case demonstrates the need for vigilant monitoring for opportunistic infections and malignancy when JAK inhibitors are utilized in SOT recipients and consideration for increased surveillance of BKPyV. Ongoing research and accumulated clinical experience are vital for understanding the implications of JAK inhibitor in SOT recipients.

ORCID iD

Laura Bywater https://orcid.org/0009-0009-6299-194X

Consent to Participate

Written informed consent was obtained from the patient for publication of this case report.

Consent for Publication

Written informed consent for publication of this case was obtained from the patient.